In recent years, the number of patients with metabolic syndrome such as type II diabetes, hyperinsulinemia, dyslipidemia, adiposity, hypertension or atherosclerotic disease has been increasing around the world due to reasons such as changes in lifestyles. Patients with metabolic syndrome have a several-fold increased risk of coronary artery disease, cerebral infarction and cerebral hemorrhage and are further affected with chronic complications such as nephropathy, neuropathy and retinopathy. The increase in the number of patients with complications has been a major cause of rising medical costs (Non-Patent Document 1).
Recent researches have shown that ligands acting on PPARγ are useful for the prevention or improvement of a pathology called metabolic syndrome such as type II diabetes, hyperinsulinemia, dyslipidemia, adiposity, hypertension, atherosclerotic disease or insulin resistance (Non-Patent Document 2). Ligands acting on PPARγ inhibit the production of inflammatory cytokines (Non-Patent Documents 3 and 4) and induce apoptosis to inhibit the growth of cancer cells (Non-Patent Document 5). Therefore, the ligands are also useful for the prevention or improvement of inflammatory disease or cancer. Specific examples of the ligands activating PPARγ include pioglitazone (Non-Patent Document 6) and rosiglitazone (Non-Patent Document 7) classified into thiazolidinedione drugs already medically used in the treatment of type II diabetes. These thiazolidinedione drugs have side effects such as fluid retention, body weight increase and increased risks for heart disease. Therefore, safer pharmaceuticals have been desired to be developed (Patent Document 1). Many researchers have now been researching and developing pharmaceuticals with an aim to prevent or improve insulin resistance, diseases caused by inflammation or the like, or metabolic syndrome through researches of ligands activating or inhibiting PPARα, PPARγ or PPARδ (Non-Patent Document 8).
Patent Document 2 describes compounds having an alkoxy group, a (substituted) phenyloxy group, a pyridyloxy group or the like bonded to the 6-position of a benzimidazole group as derivatives having the same skeleton as in the compounds of the present invention, and use of those compounds as therapeutic agents for diabetes, hyperglycemia or the like. However, in the synthetic examples in this document, the sole pyridyloxy group at the 6-position of the benzimidazole group is an unsubstituted 3-pyridyloxy group. On the other hand, in the compounds of the present invention, a pyridyloxy group having 1 to 3 substituent(s) is bonded to the 6-position of a benzimidazole group.    Patent Document 1: WO 2004/014308    Patent Document 2: WO 2008/126732    Non-Patent Document 1: Annual Reports in Medicinal Chemistry, 39, 41-56 (2004)    Non-Patent Document 2: Annual Reviews of Medicine, 53, 409-435 (2002)    Non-Patent Document 3: Nature, 391, 79-82 (1998)    Non-Patent Document 4: Nature, 391, 82-86 (1998)    Non-Patent Document 5: Biochemical and Biophysical Research Communications, 270, 400-405 (2000)    Non-Patent Document 6: CHEMICAL & PHARMACEUTICAL BULLETIN, 39, 1440-1445 (1991)    Non-Patent Document 7: Bioorganic and Medicinal Chemistry Letter, 4, 1181-1184 (1994)    Non-Patent Document 8: Annual Reports in Medicinal Chemistry, 38, 71-80 (2003)